Alcohol Impairs Immunometabolism and Promotes Naïve T Cell Differentiation to Pro-Inflammatory Th1 CD4+ T Cells

Abstract

CD4+ T cell differentiation to pro-inflammatory and immunosuppressive subsets depends on immunometabolism. Pro-inflammatory CD4+ subsets rely on glycolysis, while immunosuppressive Treg cells require functional mitochondria for their differentiation and function. Previous pre-clinical studies have shown that ethanol (EtOH) administration increases pro-inflammatory CD4+ T cell subsets; whether this shift in immunophenotype is linked to alterations in CD4+ T cell metabolism had not been previously examined. The objective of this study was to determine whether ethanol alters CD4+ immunometabolism, and whether this affects CD4+ T cell differentiation. Naïve human CD4+ T cells were plated on anti-CD3 coated plates with soluble anti-CD28, and differentiated with IL-12 in the presence of ethanol (0 and 50 mM) for 3 days. Both Tbet-expressing (Th1) and FOXP3-expressing (Treg) CD4+ T cells increased after differentiation. Ethanol dysregulated CD4+ T cell differentiation by increasing Th1 and decreasing Treg CD4+ T cell subsets. Ethanol increased glycolysis and impaired oxidative phosphorylation in differentiated CD4+ T cells. Moreover, the glycolytic inhibitor 2-deoxyglucose (2-DG) prevented the ethanol-mediated increase in Tbet-expressing CD4+ T cells but did not attenuate the decrease in FOXP3 expression in differentiated CD4+ T cells. Ethanol increased Treg mitochondrial volume and altered expression of genes implicated in mitophagy and autophagosome formation (PINK1 and ATG7). These results suggest that ethanol impairs CD4+ T cell immunometabolism and disrupts mitochondrial repair processes as it promotes CD4+ T cell differentiation to a pro-inflammatory phenotype.

Nutraceuticals as Potential Therapeutic Modulators in Immunometabolism

“…Thus, similar to other leukocytes, such as APCs, Th17 cells use glycolysis for effector inflammatory function; however, when this metabolic pathway is blocked, T cells become Treg cells [ 85 ]. In a recent study, McTernan et al demonstrated through in vitro assay that ethanol alters naive T cell metabolism with an increase in glycolysis and impaired OXPHOS, which disrupts mitochondrial repair processes and promotes Th1 CD4 + T lymphocytes [ 86 ]. Jones et al showed the main metabolic pathways for different functions in human CD4 + and CD8 + T cells.…”

Prevalence of Lymphopenia in the American Population: Insights from Demographic, BMI, and Lifestyle Factors

“…Alcohol consumption has been associated with damage to CD4 + T cell immune metabolism, hindrance of mitochondrial repair processes, and the promotion of the differentiation of CD4 + T cells into an in ammatory phenotype 35,36 . Exercise can also in uence lymphocytes in the body, potentially reducing the frequency of aged klRG1 + T cells and helping maintain the proportion of CD4 + naïve T cells, which is indicative of successful rather than maladaptive T cell aging 37,38 . Exercise can also in uence lymphocytes in the body, potentially reducing the frequency of aged klRG1 + T cells and helping maintain the proportion of CD4 + naïve T cells, which is indicative of successful rather than maladaptive T cell aging 39,40 .…”

Alcohol and the mechanisms of liver disease

“…Altering differentiation direction of T‐cell subsets is another way that alcohol metabolism intervenes T‐cell functions. Alcohol and catabolic product acetaldehyde have been reported capable of modulating signaling of PI3K/Akt and MAPK pathways via increasing NADP+, skewing the balance between Th1 and Th2 cells towards a Th2‐dominant immune response, leading to decreased Th1‐mediated immune surveillance in the liver, while inhibiting the differentiation of Th1 and Th17 cells 47,48 . This results in a shift toward an anti‐inflammatory response and impaired clearance of pathogens, leading to impaired immune surveillance and increased susceptibility to infection in the liver.…”